Marjolein S. de Bruin-Weller

Enteric-coated mycophenolate sodium versus cyclosporin A as long-term treatment in adult patients with severe atopic dermatitis: A randomized controlled trial

BACKGROUND Cyclosporin A (CsA) is frequently used in the treatment of severe atopic dermatitis (AD). Enteric-coated mycophenolate sodium (EC-MPS) may be an alternative with equal efficacy and fewer side effects. OBJECTIVE The aim of this observer-blinded randomized controlled trial was to compare EC-MPS with CsA as long-term treatment in adult patients with severe AD. METHODS Fifty five patients with AD were treated with CsA (5 mg/kg) in a 6-week run-in period. Thereafter, patients either received CsA (3 mg/kg; n = 26) or EC-MPS (1440 mg; n = 24) during a maintenance phase of 30 weeks and there was a 12-week follow-up period. Disease activity was measured using the objective SCORAD and serum thymus and activation-regulated chemokine (TARC) levels and side effects were registered. RESULTS During the first 10 weeks the objective SCORAD and serum TARC levels in the EC-MPS study arm were higher in comparison with the CsA study arm. In addition, 7 of the 24 patients treated with EC-MPS required short oral corticosteroid courses. During maintenance phase disease activity was comparable in both study arms. Side effects in both study arms were mild and transient. After study medication withdrawal, disease activity of the patients in the CsA study arm significantly increased compared with the EC-MPS study arm. LIMITATION The nonblinding of patients and prescriber of rescue medication are limitations. CONCLUSIONS This study shows that EC-MPS is as effective as CsA as maintenance therapy in patients with AD. However, clinical improvement with EC-MPS is delayed in comparison with CsA. Clinical remission after stopping EC-MPS lasts longer compared with CsA.

Towards global consensus on outcome measures for atopic eczema research: results of the HOME II meeting

The use of nonstandardized and inadequately validated outcome measures in atopic eczema trials is a major obstacle to practising evidence‐based dermatology. The Harmonising Outcome Measures for Eczema (HOME) initiative is an international multiprofessional group dedicated to atopic eczema outcomes research. In June 2011, the HOME initiative conducted a consensus study involving 43 individuals from 10 countries, representing different stakeholders (patients, clinicians, methodologists, pharmaceutical industry) to determine core outcome domains for atopic eczema trials, to define quality criteria for atopic eczema outcome measures and to prioritize topics for atopic eczema outcomes research. Delegates were given evidence‐based information, followed by structured group discussion and anonymous consensus voting. Consensus was achieved to include clinical signs, symptoms, long‐term control of flares and quality of life into the core set of outcome domains for atopic eczema trials. The HOME initiative strongly recommends including and reporting these core outcome domains as primary or secondary endpoints in all future atopic eczema trials. Measures of these core outcome domains need to be valid, sensitive to change and feasible. Prioritized topics of the HOME initiative are the identification/development of the most appropriate instruments for the four core outcome domains. HOME is open to anyone with an interest in atopic eczema outcomes research.

Long-term management of moderate-to-severe atopic dermatitis with dupilumab and concomitant topical corticosteroids (LIBERTY AD CHRONOS): a 1-year, randomised, double-blinded, placebo-controlled, phase 3 trial

BACKGROUND Dupilumab (an anti-interleukin-4-receptor-α monoclonal antibody) blocks signalling of interleukin 4 and interleukin 13, type 2/Th2 cytokines implicated in numerous allergic diseases ranging from asthma to atopic dermatitis. Previous 16-week monotherapy studies showed that dupilumab substantially improved signs and symptoms of moderate-to-severe atopic dermatitis with acceptable safety, validating the crucial role of interleukin 4 and interleukin 13 in atopic dermatitis pathogenesis. We aimed to evaluate the long-term efficacy and safety of dupilumab with medium-potency topical corticosteroids versus placebo with topical corticosteroids in adults with moderate-to-severe atopic dermatitis. METHODS In this 1-year, randomised, double-blinded, placebo-controlled, phase 3 study (LIBERTY AD CHRONOS), adults with moderate-to-severe atopic dermatitis and inadequate response to topical corticosteroids were enrolled at 161 hospitals, clinics, and academic institutions in 14 countries in Europe, Asia-Pacific, and North America. Patients were randomly assigned (3:1:3) to subcutaneous dupilumab 300 mg once weekly (qw), dupilumab 300 mg every 2 weeks (q2w), or placebo via a central interactive voice/web response system, stratified by severity and global region. All three groups were given concomitant topical corticosteroids with or without topical calcineurin inhibitors where inadvisable for topical corticosteroids. Topical corticosteroids could be tapered, stopped, or restarted on the basis of disease activity. Coprimary endpoints were patients (%) achieving Investigators Global Assessment (IGA) 0/1 and 2-point or higher improvement from baseline, and Eczema Area and Severity Index 75% improvement from baseline (EASI-75) at week 16. Week 16 efficacy and week 52 safety analyses included all randomised patients; week 52 efficacy included patients who completed treatment by US regulatory submission cutoff. This study is registered with ClinicalTrials.gov, NCT02260986. FINDINGS Between Oct 3, 2014, and July 31, 2015, 740 patients were enrolled: 319 were randomly assigned to dupilumab qw plus topical corticosteroids, 106 to dupilumab q2w plus topical corticosteroids, and 315 to placebo plus topical corticosteroids. 623 (270, 89, and 264, respectively) were evaluable for week 52 efficacy. At week 16, more patients who received dupilumab plus topical corticosteroids achieved the coprimary endpoints of IGA 0/1 (39% [125 patients] who received dupilumab plus topical corticosteroids qw and 39% [41 patients] who received dupilumab q2w plus topical corticosteroids vs 12% [39 patients] who received placebo plus topical corticosteroids; p<0·0001) and EASI-75 (64% [204] and 69% [73] vs 23% [73]; p<0·0001). Week 52 results were similar. Adverse events were reported in 261 (83%) patients who received dupilumab qw plus topical corticosteroids, 97 (88%) patients who received dupilumab q2w, and 266 (84%) patients who received placebo, and serious adverse events in nine (3%), four (4%), and 16 (5%) patients, respectively. No significant dupilumab-induced laboratory abnormalities were noted. Injection-site reactions and conjunctivitis were more common in patients treated with dupilumab plus topical corticosteroids-treated patients than in patients treated with placebo plus topical corticosteroids. INTERPRETATION Dupilumab added to standard topical corticosteroid treatment for 1 year improved atopic dermatitis signs and symptoms, with acceptable safety. FUNDING Sanofi and Regeneron Pharmaceuticals Inc.

Narrowband ultraviolet B and medium-dose ultraviolet A1 are equally effective in the treatment of moderate to severe atopic dermatitis

BACKGROUND Phototherapy may be effective in atopic dermatitis (AD). Medium-dose (MD) ultraviolet (UV) A1 was introduced for the treatment of AD. Few immunohistochemical data are available pertaining to phototherapy in AD. Regulatory T cells may play a role in clearing AD. OBJECTIVES We sought to compare the clinical and immunohistochemical effects of narrowband (NB) UVB and MD UVA1 treatment in patients with AD. METHODS Thirteen adult patients with AD were included in this randomized investigator-blinded half-sided comparison study between NB UVB and MD UVA1. Disease activity was measured using the Leicester sign score. Skin biopsy specimens were taken before and after phototherapy. Regulatory T cells were stained with the forkhead box protein P3 (FoxP3). RESULTS NB UVB and MD UVA1 both significantly decreased AD severity (P < .01) and the dermal cellular infiltrate. The percentage of FoxP3(+)CD3(+) T cells did not change after NB UVB or MD UVA1 treatment. LIMITATION MD UVA1 therapy was given 3 times per week instead of the preferred regimen of 5 times per week. This was necessary to achieve good blinding of the study. CONCLUSIONS NB UVB and MD UVA1 seem equally effective in the treatment of patients with moderate to severe AD. Neither MD UVA1 nor NB UVB had an effect on the percentage of FoxP3(+)CD3(+) T cells.

Biomarkers for atopic dermatitis: a systematic review and meta-analysis.

Purpose of reviewA large number of studies investigating the correlation between severity of atopic dermatitis and various biomarkers have been published over the past decades. The aim of this review was to identify, evaluate and synthesize the evidence examining the correlation of biomarkers with disease severity in atopic dermatitis patients, something that has not been performed previously. Recent findingsThree electronic databases were systematically searched and relevant studies were selected for inclusion. A total of 222 articles, reporting on 115 different biomarkers in 30 063 patients, were critically appraised. Studies were divided into two main groups. The first group consisted of longitudinal randomized controlled trials and cohort studies, which reported measurements at multiple time points. The second contained cross-sectional studies that reported only one measurement per patient. Out of 222 articles, 108 articles reported sufficient data for meta-analysis. Only four biomarkers were eligible for meta-analysis in the longitudinal group, and nine in the cross-sectional group. SummarySerum thymus and activation-regulated chemokine (TARC) was found to be the most reliable biomarker studied, showing pooled correlation coefficients of 0.60 (95% CI 0.48–0.70) and 0.64 (95% CI 0.57–0.70) in longitudinal and cross-sectional studies, respectively. Additional biomarkers that could prove useful but require additional research include serum cutaneous T-cell attracting chemokine (CTACK), sE-selectin, macrophage-derived chemokine (MDC), lactate dehydrogenase (LDH) and interleukin (IL)-18.

Bone mineral density in children with moderate to severe atopic dermatitis

BACKGROUND Low bone mineral density (BMD) has been reported in 30.4% of adult patients with atopic dermatitis (AD). OBJECTIVE The aim of this study was to determine the prevalence of low BMD in children with moderate to severe AD and to investigate the relation between BMD and corticosteroid and cyclosporine therapy. METHODS Lumbar spine BMD was measured by dual-energy X-ray absorptiometry in 60 children (age 5-16 years) with moderate to severe AD. BMD (in g/cm(2)) was expressed in Z-scores, the number of SD above or below the mean value of an age- and sex-matched reference population. In children, low BMD was defined as a Z-score less than -2. Information on lifestyle parameters and bone fractures were collected by use of a standardized questionnaire. The cumulative dose of corticosteroids and cyclosporine therapy was calculated for the previous 5-year period. RESULTS Three patients (5%) had low BMD; one patient (1.7%) had osteoporosis. The observed prevalence of low BMD in this study (6.7%; 95% confidence interval 1.8%-16.2%) does not differ from the expected prevalence of low BMD in the general population (P = .06). Overall, use of topical corticosteroids in the previous 5 years was not associated with a decrease in BMD (Z-score). When children received additional systemic treatment (oral corticosteroids and/or cyclosporine) in the previous 5 years, BMD decreased, although the decrease was not statistically significant. Correction for lifestyle parameters did not change these associations. LIMITATIONS The number of patients studied was limited. The cumulative dose of corticosteroids and cyclosporine therapy was only registered for the previous 5 years, and relatively low amounts of topical corticosteroids were used. The definition of low BMD differs between adults (Z-score < -1) and children (Z-score < -2). Because there is no Dutch BMD reference population for children, normative BMD references were obtained from a different population (US children). CONCLUSIONS Low BMD did not occur more frequently in this population of children with moderate to severe AD compared with the general population. Use of topical corticosteroids in the previous 5 years was not associated with a decrease in BMD.

When does atopic dermatitis warrant systemic therapy?: Recommendations from an expert panel of the International Eczema Council

Background: Although most patients with atopic dermatitis (AD) are effectively managed with topical medication, a significant minority require systemic therapy. Guidelines for decision making about advancement to systemic therapy are lacking. Objective: To guide those considering use of systemic therapy in AD and provide a framework for evaluation before making this therapeutic decision with the patient. Methods: A subgroup of the International Eczema Council determined aspects to consider before prescribing systemic therapy. Topics were assigned to expert reviewers who performed a topic‐specific literature review, referred to guidelines when available, and provided interpretation and expert opinion. Results: We recommend a systematic and holistic approach to assess patients with severe signs and symptoms of AD and impact on quality of life before systemic therapy. Steps taken before commencing systemic therapy include considering alternate or concomitant diagnoses, avoiding trigger factors, optimizing topical therapy, ensuring adequate patient/caregiver education, treating coexistent infection, assessing the impact on quality of life, and considering phototherapy. Limitations: Our work is a consensus statement, not a systematic review. Conclusion: The decision to start systemic medication should include assessment of severity and quality of life while considering the individuals general health status, psychologic needs, and personal attitudes toward systemic therapies.

Moving toward endotypes in atopic dermatitis: Identification of patient clusters based on serum biomarker analysis

Background Atopic dermatitis (AD) is a complex, chronic, inflammatory skin disease with a diverse clinical presentation. However, it is unclear whether this diversity exists at a biological level. Objective We sought to test the hypothesis that AD is heterogeneous at the biological level of individual inflammatory mediators. Methods Sera from 193 adult patients with moderate‐to‐severe AD (six area, six sign atopic dermatitis [SASSAD] score: geometric mean, 22.3 [95% CI, 21.3‐23.3] and 39.1 [95% CI, 37.5‐40.9], respectively) and 30 healthy control subjects without AD were analyzed for 147 serum mediators, total IgE levels, and 130 allergen‐specific IgE levels. Population heterogeneity was assessed by using principal component analysis, followed by unsupervised k‐means cluster analysis of the principal components. Results Patients with AD showed pronounced evidence of inflammation compared with healthy control subjects. Principal component analysis of data on sera from patients with AD revealed the presence of 4 potential clusters. Fifty‐seven principal components described approximately 90% of the variance. Unsupervised k‐means cluster analysis of the 57 largest principal components delivered 4 distinct clusters of patients with AD. Cluster 1 had high SASSAD scores and body surface areas with the highest levels of pulmonary and activation‐regulated chemokine, tissue inhibitor of metalloproteinases 1, and soluble CD14. Cluster 2 had low SASSAD scores with the lowest levels of IFN‐&agr;, tissue inhibitor of metalloproteinases 1, and vascular endothelial growth factor. Cluster 3 had high SASSAD scores with the lowest levels of IFN‐&bgr;, IL‐1, and epithelial cytokines. Cluster 4 had low SASSAD scores but the highest levels of the inflammatory markers IL‐1, IL‐4, IL‐13, and thymic stromal lymphopoietin. Conclusion AD is a heterogeneous disease both clinically and biologically. Four distinct clusters of patients with AD have been identified that could represent endotypes with unique biological mechanisms. Elucidation of these endotypes warrants further investigation and will require future intervention trials with specific agents, such as biologics.

Food allergen sensitization pattern in adults in relation to severity of atopic dermatitis

BackgroundLimited data are available on the frequency of IgE mediated food sensitization and food allergy (FA) in adults with atopic dermatitis (AD).ObjectiveWe investigated the pattern of food sensitization in adults with AD in relation to AD severity using multiplexed allergen microarray.Methods211 adult patients referred between January 2010-July 2011 for evaluation of AD were unselectively included. Severity of AD was determined by therapy intensity, SASSAD-skin-score and sTARC levels. Allergen specific sIgE levels were measured by ImmunoCAP ISAC® microarray. FA was defined as convincing history taken by physician and sensitization to the corresponding allergen.ResultsSensitization to food was found in 74.4% of the AD patients, 54% had a positive history of FA and 20.4% asymptomatic sensitization. There was no association between severity of AD and frequency of food sensitization or history of FA.Sensitization to PR-10 related food allergens occurred most frequently (63.5%) and was independent from AD severity. Correspondingly, pollen-food syndrome accounted for most of the FA, being also independent from AD severity. Of all plant food allergens only sensitization to nAra h 1 was significantly more frequent in patients with severe AD. In the total group 75 (35.5%) patients with AD showed sensitization to any animal food allergen. The percentage was significantly higher in patients with severe AD (51.4%) compared to patients with mild/moderate AD (27.7%). Sensitization to cow’s milk allergens, in particular to nBos d lactoferrin, was more frequent in severe AD patients.ConclusionAD was frequently associated with food sensitization. The percentage of sensitization to animal food allergens was significantly higher in severe AD patients.

New Developments in Biomarkers for Atopic Dermatitis.

The application of biomarkers in medicine is evolving. Biomarkers do not only give us a better understanding of pathogenesis, but also increase treatment efficacy and safety, further enabling more precise clinical care. This paper focuses on the current use of biomarkers in atopic dermatitis, new developments and future perspectives. Biomarkers can be used for many different purposes, including the objective determination of disease severity, confirmation of clinical diagnosis, and to predict response to treatment. In atopic dermatitis, many biomarkers have been investigated as a marker for disease severity. Currently serum thymus and activation-regulated chemokine (TARC) is the superior biomarker for assessing disease severity. However, we have recently shown that the use of a panel of serum biomarkers is more suitable for assessing disease severity than an individual biomarker. In this overview, we will discuss alternative sources for biomarkers, such as saliva and capillary blood, which can increase the user friendliness of biomarkers in atopic dermatitis (AD). Both methods offer simple, non-invasive and cost effective alternatives to venous blood. This provides great translational and clinical potential. Biomarkers will play an increasingly important role in AD research and personalized medicine. The use of biomarkers will enhance the efficacy of AD treatment by facilitating the individualization of therapy targeting the patients’ specific biological signature and also by providing tools for predicting and monitoring of therapeutic response.